Lectin‐Like Oxidized Low‐Density Lipoprotein Receptor 1 Inhibition in Type 2 Diabetes: Phase 1 Results

Author:

Vavere Andrea L.1ORCID,Sinsakul Marvin1,Ongstad Emily L.2ORCID,Yang Ye3ORCID,Varma Vijayalakshmi1,Jones Christopher4ORCID,Goodman Joanne4,Dubois Vincent F. S.4ORCID,Quartino Angelica L.4ORCID,Karathanasis Sotirios K.2ORCID,Abuhatzira Liron1ORCID,Collén Anna5ORCID,Antoniades Charalambos6ORCID,Koren Michael J.7,Gupta Ruchi2,George Richard T.1ORCID

Affiliation:

1. Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism BioPharmaceuticals R&D, AstraZeneca Gaithersburg MD USA

2. Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism BioPharmaceuticals R&D, AstraZeneca Gaithersburg MD USA

3. Early CVRM Biometrics, Research and Early Development, Cardiovascular, Renal and Metabolism BioPharmaceuticals R&D, AstraZeneca Gaithersburg MD USA

4. Clinical Pharmacology & Quantitative Pharmacology Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca Gothenburg Sweden

5. Projects, Research and Early Development, Cardiovascular, Renal and Metabolism BioPharmaceuticals R&D, AstraZeneca Gothenburg Sweden

6. Division of Cardiovascular Medicine, Radcliffe Department of Medicine University of Oxford United Kingdom

7. Jacksonville Center for Clinical Research (JCCR) Jacksonville FL USA

Abstract

Background Blockade of the lectin‐like oxidized low‐density lipoprotein receptor‐1 (LOX‐1) is a potentially attractive mechanism for lowering inflammatory and lipid risk in patients with atherosclerosis. This study aims to assess the safety, tolerability, and target engagement of MEDI6570, a high‐affinity monoclonal blocking antibody to LOX‐1. Methods and Results This phase 1, first‐in‐human, placebo‐controlled study (NCT03654313) randomized 88 patients with type 2 diabetes to receive single ascending doses (10, 30, 90, 250, or 500 mg) or multiple ascending doses (90, 150, or 250 mg once monthly for 3 months) of MEDI6570 or placebo. Primary end point was safety; secondary and exploratory end points included pharmacokinetics, immunogenicity, free soluble LOX‐1 levels, and change in coronary plaque volume. Mean age was 57.6/58.1 years in the single ascending doses/multiple ascending doses groups, 31.3%/62.5% were female, and mean type 2 diabetes duration was 9.7/8.7 years. Incidence of adverse events was similar among cohorts. MEDI6570 exhibited nonlinear pharmacokinetics, with terminal half‐life increasing from 4.6 days (30 mg) to 11.2 days (500 mg), consistent with target‐mediated drug disposition. Dose‐dependent reductions in mean soluble LOX‐1 levels from baseline were observed (>66% at 4 weeks and 71.61–82.96% at 10 weeks in the single ascending doses and multiple ascending doses groups, respectively). After 3 doses, MEDI6570 was associated with nonsignificant regression of noncalcified plaque volume versus placebo (−13.45 mm 3 versus −8.25 mm 3 ). Conclusions MEDI6570 was well tolerated and demonstrated dose‐dependent soluble LOX‐1 suppression and a pharmacokinetic profile consistent with once‐monthly dosing. Registration URL: https://clinicaltrials.gov/ ; Unique identifier: NCT03654313.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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